2,3;3a,12b - tetrahydro - 8h - dibenzo (3,4;6,7)cyclohept(1,2-d)oxazoles and derivatives



United States Patent 3,478,048 2,3;3a,12b TETRAHYDRO 8H DIBENZO[3,4;6,7]CYCLOHEPT[1,2-d]0XAZOLES AND DERIVATIVES Albrecht Edenhofer,Riehen, and Hans Spiegelberg, Basel, Switzerland, assignors toHolfmann-La Roche Inc., Nutley, N.J., a corporation of New Jersey 4 NoDrawing. Filed Jan..3, 1966, Ser. No. 517,893 Claims priority,application Switzerland, Jan. 8, 1965, 232/65; Jan. 14, 1965, 525/65;Dec. 17, 1965, 525/65 Int. Cl. C07d 85/06; C07c 131/00, 119/00 US. Cl.260-307 7 Claims ABSTRACT OF THE DISCLOSURE 2,3;3a,12b-tetrahydro 8Hdibenzo[3,4;6,7]cyclohept- [l,2-d]oxazoles and dibenzo [a,d]cyclohept[1,4]dienes bearing, for example, substituents at the 10- and11-positions, are prepared, inter alia, from the correspondingdibenzocycloheptatrienones. The products are useful as antidepressants.

The present invention relates to novel therapeutically active compounds.More particularly, the present invention relates to novel derivatives ofdibenzocycloheptene. The compounds of this invention aredibenzocycloheptene derivatives of the formula wherein A and B each is,individually, hydrogen, halogen, lower alkyl, lower alkoxy,trifluoromethyl, lower alkylmercapto, lower alkanoyl, sulfamoyl, loweralkylsulfamoyl or lower alkylsulfonyl; Z is oxo, oxo ketalized withlower alkanol or lower alkylenedioxy; R is hydrogen, lower alkyl oraryl; R is hydrogen, lower alkyl or aryl; R taken together with R isthio, oxo or imino; R is hydrogen or lower alkyl; and pharmaceuticallyacceptable acid addition salts thereof.

The substituents on each of the benzene rings of the compound of FormulaI can be one or more halogen atoms, e.g., fluorine, chlorine, bromineand iodine, chlorine and bromine beingespecially preferred; straight orbranched chain lower alkyl groups with up to 7 carbon atoms, e.g.,methyl, ethyl, butyl, hexyl; lower alkoxy groups with up to 7 carbonatoms, e.g., methoxy, ethoxy, heptoxy; lower alkylmercapto groups withup to 7 carbon atoms e.g., methylmercapto, ethylmercapto; lower'alkanoyl groups with up to 7 carbon atoms, e.g., acetyl, caproyl; loweralkylsulfonyl, e.g., methylsulfonyl, hexyl- ,sulfonyl; sulfamoyl orlower alkylsulfamoy, e.g., methylsulfamoyl.

The term lower alkyl" as employed in this application includes loweralkyl groups of up to 7 carbon atoms, e.g., methyl, ethyl, isopropyl,etc. The term aryl includes phenyl, benzyl, and also includes alkarylgroups, e.g., tolyl, xylyl and isopropylphenyl, etc.,The term cycloalkylincludes cyclic hydrocarbons of up to 7 carbon atoms which can besubstituted lower alkyl groups, i.e., lower alkyl-cycloalkane, e.g.,methylcyclopropyl, or cycloalkyl-lower alkylene, e.g.,cyclopropylmethylene. The term halogen or halo as used herein includesfluorine, chlo- 3,478,048 Patented Nov. 11, 1969 O-lower alkyl O-loweralkyl As indicated, there can be used as ketal-forrning substances loweralkanols and lower alkylene glycols, for example, methanol, ethanol, orethylene glycol.

The oxazolidine compounds of Formula I can be prepared by reactingcompounds of the formula:

0H N-H 9 1 I 1 B H wherein A, B, R and Z have the same meaning as above,with a cyclizing agent in a conventional manner.

The cyclizing agents which can be employed are known and include, forexample, cyanogen halide, aldehydes or ketones, carbonates and carbonicacid halides. The product on cyclization of compounds of Formula II isthe corresponding oxazolidine. For example, cyclization of compounds ofFormula II, wherein Z is oxo, with a cyanogen halide, e.g., cyanogenbromide, results in the preparation ofZ-imino-dibenzocyclohept-oxazolidinones. The above reaction ispreferably conducted in the presence of an inert solvent at roomtemperature. Cyclization may be effected with other reactants known forthat purpose, e.g., an aldehyde or ketone, for example, a lower alkanoicacid aldehyde, e.g., acetaldehyde, or a di-lower alkyl ketone, e.g.,acetone, or a cyclolower alkyl ketone, e.g., cyclohexanone. Whenemploying an aldehyde or ketone it is preferable to conduct the reactionat reflux temperature under dehydration conditions. When acetone is thecyclization agent and Z is oxo,2-dimethyl-dibenzo-cycloheptoxazolidinone is obtained. If Z is aketalized oxo in the starting material, the product is the correspondingketal. Other known cyclization agents include the carbonates, e.g.,diethylcarbonate and the carbonic acid halides, e.g., phosgene. Whenemploying a carbonate, it is preferable to heat the reaction mixture toreflux temperature in the presence of a trace of metallic sodium. Whenemploying carbonic acid halides, it is preferable to conduct thereaction at room temperature, in the presence of an acid-binding agent,e.g., lead carbonate. With either diethylcarbonate or phosgene as thecyclization agent, the corresponding2-oxo-dibenzocyclohept-oxazolidinones or ketals thereof are obtained.

In an embodiment related to that discussed above, the invention alsoprovides novel compounds of the formula III wherein A, B and Z have thesame meaning as above; P is hydrogen, hydroxyl, lower alkanoyloxy orhalogen; P is hydrogen, or together with P is oxo; Q and Q each is,individually, hydrogen, lower alkyl, cyclo-lower alkyl, aryl, loweraralkyl, lower alkanoyl, cyclo-lower alkanoyl, aroyl, halogen,halo-lower akyl, halo-lower alkanoyl, halo-aryl, halo-lower aralkyl,halo-aroyl, hydroxy-lower alkyl, hydroxy-lower alkanoyl, hydroxyaralkyl,hydroxy-aroyl, amino, lower alkylamine, di-lower alkylamine, halo-loweralkylamine, halo-di-lower alkylamino, hydroxy-lower alkylamino,hydroxy-di-lower alkylamino; Q and Q taken together with the nitrogenatom, is a heterocyclic ring of 5 to 6 members or a heterocyclic ring 5to 6 members having a lower alkyl substituent; and pharmaceuticallyacceptable acid addition salts thereof.

As employed herein the term lower alkanoyl includes the acyl moiety oflower alkyl carboxylic acids with up to 7 carbon atoms, i.e., acidsdevoid of the carboxy proton, e.g., formyl, acetyl, propionyl, butanoyl,etc.; cyclolower alkanoyl includes cyclo-lower alkyl carboxylic acids,e.g., cyclopropionyl; aroyl includes, for example, benzoyl, phenacetyland phthaloyl; and lower aralkyl includes, for example, benzyl andphenethyl. The substituent groups named heretofore can each,individually, also be substituted with, for example, hydroxyl groups,e.g., 3-hydroxy propylene, hydroxy-benzoyl; or with halogen atoms, e.g.,chloropropyl or bromobenzyl; or with any combination of the aforegoing.Furthermore, the aryl moieties named above can bear two or moresubstituents, whether identical or not, or any of the relative positionsof the phenyl group, e.g., ortho, meta and para. When either Q or Q isamino or substituted amino linked directly to the nitrogen atom, itforms a hydrazine residue, e.g., methylhydrazino, ethylhydrazino,isopropylhydrazino, etc. As indicated above, Q and Q together with thenitrogen atom, can represent a heterocyclic ring of 5 to 6 members or aheterocyclic ring of 5 to 6 members having a lower alkyl substituent.That heterocyclic ring can contain other hetero atoms besides nitrogen,e.g., oxygen or sulfur. Examples of such heterocyclic rings arepiperidino, piperazino, pyrrolidino, morpholino, imidazolino,1(2H)pyrimidino, 1(2H) isothiazolino, pyrazolino, pyrazolidino, methylpiperidino, hexyl piperidino, pentyl morpholino, etc.

The compounds of Formula III are generic to those of Formula II and canbe prepared from the corresponding dibenzocycloheptatrienones. Forexample, compounds of the formula:

wherein A, B and Z have the same meaning as above; R, \V

. 4 pedient to work in a closed system. The product resulting is acompound of the formula:

wherein A, B, Z, R R and R have the same'meaning as above.

Compounds of Formula VI are identical with compounds of Formula VII whenR, is hydroxyl.

The compounds of Formula VI can also be obtained in a more directmanner. For example, with reference to compounds of Formula V wherein Rand R together form an oxygen bridge, i.e., an epoxy linkage, the epoxycompounds can be directly aminated in a conventional manner to thecorresponding IO-hydroxy-ll-lower alkylamino compounds of Formula VI.Direct amination can be effected by, for example, reacting the10,11-epoxy-dibe'nzo[l,2;4,5]cycloheptanones or their ketals with loweralkylamine, preferably at a temperature between about and C. andadvantageously in the presence of a solvent, e.g., ethanol or dioxane.With amines volatile at the reaction temperature, it is convenient towork in a closed system under pressure. If ammonia is used in lieu ofthe lower alkylamine, then the corresponding 10-hydroxy-ll-aminocompound will be obtained. The epoxide starting materials, i.e., whereR, and R in Formula V are taken together to form an oxygen bridge, canbe prepared from the corresponding dibenzocycloheptatrienones depictedbyFormula IV, as described in Bull. Soc. Chim. France (1960), p. 404, oras described hereinafter in Example 6. In another variation, the epoxidestarting materials can be used to prepare the IO-hydroxy-ll-halocompounds depicted by Formula V by reacting the epoxides with amagnesium halide, e.g., magnesium bromide.

The l0-hydroxy-l l-halo compounds of Formula V prepared by either of theaforesaid methods, i.e., halogenation of compounds of Formula IV ortreatment of the corresponding epoxides with a magnesium halide, can beconverted into the corresponding 10-oxo-11-halo compounds. ThelO-oxo-ll-halo compounds are depicted by Formula V when R, and R takentogether represent an oxo group. The IO-oxo-ll-halo compounds can beprepared by reacting the corresponding 10-hydroxy-11-halo compounds witha dichromate/sulfuric acid reagent, e.g., sodium dichromate/ sulfuricacid.

Compounds of Formula V wherein R and R taken together represent an oxogroup can be aminated in the same manner as indicated above. Compoundsof Formula V wherein R and R taken together form an oxygen bridge can beaminated preferably at a higher temperature than amination ofcorresponding non-epoxy compounds, i.e., between 100 and 150 C., and thepresence of asolvent such as an alcohol, i.e., lower alkanol, e.g.,ethanol, or any ether, e.g., dioxane, in the reaction mixture isdesirable. The reaction can also be conducted with water as the reactionmedium. When employing amines volatile at the reaction temperature, itis expedient to work in a closed system under pressure.

Hence, amination of compounds of the formula VII is hydrogen, hydroxyl,lower alkanoyloxy or halogen; P

is hydrogen or together with P isoxo; and P is halogen or together withP is oxygen with an amine or a substituted amine, e.g., lower alkylamineor lower alkanoylamine, produces compounds of Formula III. If desired,subsequent to amination, the amino moiety at position-ll can be furthersubstituted, e.g., acylated to form an amide.

Compounds of Formula .111 can be further reacted to produce a variety ofderivatives. For example, when P in Formula III is hydroxyl, reactionwith thionyl chloride will result in the replacement of the hydroxylgroup with chlorine. The resulting.10-chloro-11-amino derivative ofFormula III thus obtained can, when either Q, or Q is hydrogen or whenboth Q and Q are hydrogen, be acylated to form the correspondingIO-chloro-ll-lower alkanoylamino compound of Formula III. In addition,if desired, the chlorine atom in the above -chloro-l1-amino derivativeof Formula III can be removed prior to acylation and thereby an ll-aminoor an ll-lower alkanoylamino derivative of Formula'III can be obtained.In like manner, when P is hydroxy and either Q or Q is hydrogen, or bothare hydrogen, acylation can be conducted in a conventional manner,preferably under mild conditions, to obtain a 10-hydroxy-l l-loweralkanoylamino derivative ofFormula III. The latter can then be reactedwith a halogenation agent, e.g., thionyl chloride, to obtain thecorresponding 10-halo-11-lower alkanoylamino derivative of Formula IIIwith retention of the steric configuration. Alternatively, theIO-hydroXy-lllower alkanoylamino derivative of Formula III, obtained byconventional acylation as indicated above, can be further acylated atthe 10-position to derive the corresponding 10-lower alkanoyloxy-ll-lower alkanoylamino derivative. By acylation under high temperatures,the latter compound, namely, the 10 lower alkanoyloxy-ll-loweralkanoylamino derivative, can be obtained directly from thecorresponding 10-hydroxy-11-amino compound of Formula III. In anothervariation, the IO-hydroxy-ll-amino compounds of Formula III can beacylated to form the corresponding IO-hydroxy-ll-halo-loweralkanoylamino derivative. Also, when Q and Q are each a substituentother than hydrogen and P is hydroxy, acylation will result in thepreparation of the corresponding 10-lower alkanoyloxy-l l-di-substitutedamino derivatives.

The compounds of Formula III can exist in two epimeric form which differin the configuration of the substituents at carbon atom-10. Thecompounds of Formula VII wherein P is hydroxy and P is halogen exist inthe trans form. When these compounds are aminated to form compounds ofFormula III, the trans form at carbon-1 0 is maintained. Thetrans-10-hydroxy-l l-amino compounds of Formula III thus obtained, whenQ and Q are each hydrogen, can be converted into the correspondingcis-lO- hydroxy-ll-amino compounds in a conventional manner, forexample, through an intermediate containing an oxazoline ring; that is,the trans-IO-hydroxy-l l-amino-compound can be acylated, for example, byN-benzoylation, and subsequently cyclized with inversion ofthe.substitucuts at carbon atom-10. The oxazoline ring can then becleaved by acid hydrolysis resulting in the formation of thecorresponding cis-lO-hydroxy-lhamino compound. Thetrans-lO-hydroxy-ll-amino compounds of Formula III (when the amino groupis not acylated) canbe converted into the correspondingcis-lO-halo-ll-amino compounds by reaction of the former with thionylchloride. The reaction results in both the replacement of the hydroxylgroup in the 10-position by chlorine and an inversion at the10-position.

The compounds of this invention will form pharmaceutically acceptableacid addition salts with bbth inorganic and organic acids. For example,salts can be prepared by treatment of the reaction products withhydrohalic acids, e.g., hydrochloric acid, hydrobromic'acid or withother mineral acids, e.g., sulfuric acid, phosphoric acid or nitric acidor with organic acids, e.g., tartaric acid, citric acid, oxalic acid,camphor-sulfonic acid,

ethane-sulfonic acid, para-toluenesulfonic acid, salicylic acid,ascorbic acid, maleic'acid, mandelic acid, etc. The preferred salts arethose formed from the hydrohalides, especially the hydroclorides. Thepharmaceutically acceptable acid addition salts are preferably preparedby treatment of the base with the corresponding acid in an inertsolvent. Salts with non -pharmaceutical1y acceptable acids can beconverted into, salts with pharmaceutically acceptable acids byneutralization followed by reaction with pharmaceutically acceptableacids or by conventional metathetic reaction.

The compounds of this invention are pharmaceutically useful, forexample, as antidepressants, e.g., to reverse both endogenous andexogenous depression of the central nervous system.

Outstanding among th agents useful to reverse depression of the centralnervous system are 2-imino-dibenzocyclohept oxazolidinone, trans 10hydroxy-llacetamidodibenzo[a,d]cyclohepta[1,4]dien 5 one andd,l-11-piperazino-dibenzo[a,d]cyclohepta[1,4]diene 5,10- dione. Thecompounds of this invention exhibit remarkably slight anticholinergicside effects. They can be administered either as the free base or in theform of their pharmaceutically acceptable acid addition salts or can beadministered in a conventional pharmaceutical formulation. Thatformulation can contain an inert organic or inorganic pharmaceuticalcarrier suitable for enteral or parenteral application, e.g., water,gelatin, lactose, starch, magnesium stearate, talc, vegetable oils,gums, olein alcohols, Vaseline, etc. The pharmaceutical preparations canbe administered in solid form, e.g., tablets, dragees, suppositories, orcapsules or in liquid form, e.g., solutions, suspensions or emulsions.They may be sterilized and may contain additives for preserving theirshelf life, e.g., antioxidants or stabilizing, wetting or emulsifyingagents or salts for adjusting the osmotic pressure or buffers. Compoundsof this invention can be combined with other therapeutically valuablematerials in a variety of pharmaceutical preparations.

The present invention is further disclosed in the following examples,which are illustrative but not limit-ative thereof. All temperatures arein degrees centigrade.

EXAMPLE 1 crystallized out cruded,l-tr'ans-2-imino2,3;3a,l2b-tetrahydro-SH-dibenfio 3,4;6,7] cyclohept[1,.2-dfoxazole-8-one hydrobromide which melted at 224-225 C.(decompositio n' after reprecipitation from methanol/ether.

In an analogous manner there was obtained, when employingd,l-trans-10-hydroxy-1l-methylamino 10,11 dihydro-dibenzo a,d]cyclohepten-S-one, d,l-trans-2-imino- 3-methyl-2,3;3a,IZb-tetrahydro 8Hdibenzo[3,4;6,7] cyclohept[1,2-d]oxazole-8-one hydrobrornide, M.P. 264-265 C. (decomposition).

The d,I-trans-10-hydroxy-11amino(or methylamino) 1 0, l1-dihydro-dibenzo[a,d] cyclohepten-S-one employed in Example 1 asstarting compound can, for example, be matiufactured as follows:

(a) gms. of 10,11-epoxy-10,l.l-dihydro-dibenzo [a,d]cyclohepten-5-oneand 1000 ml. of aqueous ammoriia .(about 28%) were reacted in a 2 literlined stainless steel shaking autoclave and shaken at 110 C. for 1 hour.After cooling, the crude product was filtered off by suction, washedwith water and dissolved with cooling in 3 N aqueous hydrochloric acid.The solution was extracted with 200 ml. of chloroform, filtered overactive charcoal and made alkaline with 3 N aqueous ammonia whilesimultaneously cooling the solution in an ice bed. Thed,l-trans-lO-hydroxy-l1-amino-10,1 l-dihydro-dibenzo[a,d]cyclohepten--one which crystallized out was filtered ofl by suctionand thoroughly washed with water. The base melted at 205206 C. afterrecrystallization from ethanol.

(b) 11.1 gms. of 10,11-epoxy-10,1l-dihydro-dibenzo[a,dJcyclohepten-S-one and 50 liters of dioxane were reacted with 15.5gms. of methylamine in a 0.3 liter stainless steel autoclave withstirring device and heated at 110 C. with stirring for 8 hours. Aftercooling, the volatile portions were evaporated under reduced pressure,the residue was dissolved in absolute alcohol, made congoacid red withalcoholic hydrochloric acid and the hydrochloride precipitated withether. For conversion into the free base, the hydrochloride wasdissolved in water, made alkaline with aqueous ammonia, wherebyd,l-trans-lG- hydroxy-ll-rnethylamino 10,11 dihydro-dibenzo[a,d]oyclohepten-S-one crystallized out. After a few hours, the base wasfiltered off and washed with water. After recrystallization fromethanol, it melted at 198-199 C.

Under the reaction conditions described immediately above, 10,11epoxy-dibenzo[a,d]cyclohepta[1,4]dien-5- one can be reacted with furtherprimary and secondary EXAMPLE 2 A strong stream for phosgene was passedat room tem. perature with stirring for 3 hours into a suspension of 5.1gms. ofd,l-trans-lO-hydroxy-ll-methylamino-10,l1-dihydro-dibenzo[a,dJcyclohepten-S-oneand 13.4 gms. of lead (2) carbonate in 400 gms. of alcohol-freechloroform. Excess phosgene was removed by passing in air. The reactionmixture was subsequently filtered off by suction, and the filtrationresidue was washed with 50 ml. of chloroform. The filtrate wasevaporated to dryness under red-uced pressure. Thed,l-trans-3-methyl2,3;3a,12b-tetrahydro-8H-dibenzo[3,4;6,7]cyclohept[1,2d] oxazole-2,8-dione, which remained behind, melted at 169-171" C. afterrecrystallization from methanol.

EXAMPLE 3 10.2 gms. of d,l-transdO-hydroxy-ll-methylamino-IO,1l-dihydro-dibenzo[a,d]cyclohepten-5-one and 100 ml. of absolute acetonewere admixed with 2 gms. of p-toluenesulfonic acid and the reactionmixture was heated at reflux for 48 hours. The reaction mixture wassubsequently evaporated to dryness under reduced pressure. The 2,2,3-trimethyl2,3;3a,1Zb-tetrahydro-SH-dibenzo[3,4;6,7]cyclohept[1,2-d]0xazo1e-8-onewhich remained behind melted at 122-123 C. after severalrecrystallizations from methanol.

EXAMPLE 4 2.5 gms. of d,l-trans-lO-hydrbxy-l1-methylamino-10,l 1-dihydro-SH-dibenzo[a,d]cyclohepten-5-one in ml. of water were reactedwith 8 gms. of carbon disulfide in 20 ml. of 3 N sodium hydroxide atroom temperature with constant stirring for 2 days. Initially thereaction mixture consisted of a complete solution, but toward the end ofthe reaction time, a reaction product crystallized out. The

carbon disulfide was then evaporated off under reduced pressure. Theresidue was filtered by suction and washed with water. The product,d,1-trans-2-thio-3-methyl 2,3;3a, 12b tetrahydro8H-dibenzo[3,4;6,7]cyclohept[1,2-d] oxazole-S-one, was thenrecrystallized from ethanol and melted at 217 C.

EXAMPLE 5 2.5 gms. of d,l-trans-lO-hydroxy-l1-methylamino-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5-one were reacted with 1.2 gms. of'benzaldehyde in 20 ml. of absolute benzene for 16 hours at refluxtemperature. After cooling the solvent was evaporated under vacuum.Ethanol was then added to the remaining yellow oil and a crystallineprecipitate was obtained. After recrystallization from ethanol, d,1trans 2 phenyl-3-methyl-2,3;3a,12b-tetra.hydro-8H-dibenzo[3,4;6,7]cyclohept[1,2-d]oxazole-8-one was obtained and melted atl25-126 C.

EXAMPLE 6 2.5 g. ofd,l-trans-lO-hydroxy-l1-methylamino-10,1l-dihydro-5H-dibenzo[a,d]cyclohepten-S-one,20 ml. of absolute benzene, 10 ml. of acetaldehyde and 20 g. ofp-toluenesulphonic and are kept at reflux conditions for 20 hours,whereby a brown solution is formed. After cooling the reaction mixtureis added to an excess of 5% sodium carbonate solutiontthe benzene phaseis thereafter washed with water, dried over potassium carbonate and thebenzene is evaporated under reduced pressure. The oily, yellow residueis brought to crystallize in a small amount of ethanol. Afterrecrystallization from methanol there is obtained pured,l-trans-2,3-dimethyl-2,3;3a,l2b-tetrahydro 8Hdibenzo[3,4;6,7]cyclohept[l,2-d]oxazol-8-one, melting at 128 C.

EXAMPLE 7 22.2 gms. of 10,1l-epoxy-dibenzo[a,d]cyclohepta[1,4]dien-S-one were reacted with 21.8 gms. of morpholine at 150 C. 'for 3hours with stirring in a 200 ml. sulfonation flask employing athermometer, a reflux condenser and a stirrer. The epoxide was therebycompletely solubilized. After cooling, the reaction mixture wasconcentrated under reduced pressure at 60 C., the residue was dissolvedin 20 ml. of absolute ethanol (to get complete solution, the reactionmixture was heated).and made congo-acid red with alcoholic hydrochloricacid. The hydrochloride which precipitated after the addition of 800 ml.of absolute ether was permitted to stand for several hours and thenfiltered oil? by suction and washed three times with ml. of absoluteether each time. The filter residue was dissolved in about 200 ml. ofwater. The solution was filtered and made alkaline by the addition of 3N ammonia-alkaline aqueous solution. After a few hours, the precipitatedbase was filtered off by suction and. neutralized by washing with water.The.d,l-trans-lO-hydroxy-ll-morpholino-dibenzo[a,'d]cyclohepta[1,4]dien-5-onemelted at 246247 C. (decomposition) after recrystallization fromdioxane.

The epoxide used as the starting material can, for example bemanufactured as follows:

300 ml. of methanol, 8 gms. of potassium bicarbonate, 82.4 gms. ofdibenzo[a,d]cyclohepta[l,4,6]trien-5-one, 41.6 gms. of benzonitrile and50 ml. of 30% hydrogen peroxide were mixed together and intensivelystirred at room temperature in a 1000 ml. flask for 24 hours. After afurther addition of 41.6 gms. of benzonitrile and 50 m1. of 30% hydrogenperoxide in 100 ml. of methanol, the reaction mixture was further,stirred for hours, then treated with 500 ml. of water, filtered afterbrief but thorough stirring and washed with 300 ml. of a mixture ofmethanol/water 1:1. The filter residue was suspended in about 300 ml. of40% sodium bisulphite solution. The suspension was stirred for 1 hour at50 C. and then cooled and filtered. The filter residue was again washedwith a mixture of methanol/water 1:1 and dried under reduced pressure at50 C. The well-dried crude product was digested in about 500 ml. ofhigh-boiling petroleum ether, filtered therefrom and dried. Afterrecrystallization from acetic ester, the 10,11-epoxy-dibenzo [a,d]cyclopenta[1,4] dien-S-one melted at 127-130 C. v

The 10,11 epoxy dibenzo[a,d]cycloheptal[1,4]dien- 5-one can, under thereaction conditions describedin this example, be reacted, for example,with the following monoand di-substituted amines. For example, whenemploying- N-Z-hydroxyethyl-N-ethylamine, there was obtained: d,l trans10 hydroxy 11 N (2 hydroxy ethyl- N ethyl) aminodibenzo[a,d]cyclohepta[1,4]dien 5- one hydrochloride, M.P. 143-147".

Pyrrolidine, there was obtained: d,l-trans-10-hydroxy-- 11 pyrrolidinodibenzo[a,d]cyclohepta[l,4]dien 5- one, M.P. 135.

Benzylamine, there was obtained: d,l-trans-10-hydroxy- 11 benzylaminodibenzo[a,d]cyclohepta[l,4]dien 5- one alcohol, M.P. 98100.

Piperidine, there was obtained: d,l,-trans-10-hydroxy- 11 piperidinodibenzo[a,d]cyclohepta[1,4]dien 5- one, M.P. 129.

Isopropyl-hydrazine, there was obtained: d,l,trans-10- hydroxy 11 (2isopropylhydrazino) dibenz[a,d] cyclohepta[1,4]dien--one hydrochloride,M.P. 206.

. Piperazine, there was obtained: d,l-trans--hydroxy- 11 piperazinodibenze[a,d]cyclohepta[1,4]dien 5- one, M.P. 24l-243 (decomposition).

, p-Ch1orobenzylamine, there was obtained: d,l-trans- 10 hydroxy 11 (4chloro benzylamino) dibenzo [a,d]cyclohepta[1,4]dien-5-one, M.P.136-137.

Diethylamino-propylamine, there was obtained: d,ltrans 10 hydroxy 11(3-diethylaminopropylamino)- dibenzo [a,d]cyclohepta[1,4]dien-5-one,M.P. 85-87.

EXAMPLE 8 3.0 gms. of d,l trans 10-hydroxy-ll-bromo-dibenzo[a,d]cyclohepta[1,4]dien-5-one was reacted with 1.7 gms. of piperidineby heating on a water-bath for 2 hours. After cooling, the reactionmixture which thereby solidified and turned orange in color was treatedwith 50 ml. each of benzene and water and vigorously shaken until thereaction mixture had completely gone into solution. The organic phasewas washed three times with 50 ml. of water each time, dried overpotassium carbonate and made congo-acid red with ethereal hydrochloricacid, whereby the crude hydrochloride crystallized out. Theprecipitation was made complete by addition of 200- ml. of absoluteether. After standing for several hours, the reaction product wasfiltered off by suction, washed with 100 ml. of absolute ether,dissolved in a mixture of 20 ml. of water and 20 ml. of ethanol andfiltered. The filtrate was made alkaline with 3 Nammonia. Theprecipitated d,l trans IO-hydroxy-ll-piperidino-dibenzo[a,d]cyclohepta[1,4]dien-5-one melted at 129 C. after recrystallization frommethanol.

The d,l trans 10 hydroxy 11 bromo dibenzo [a,d]cyclohepta[1,4]dien-5-onewhich was employed in this example can be manufactured as follows: 6.9gms. of N-bromo-acetamide were dissolved with stirring in a mixture of100 ml. of dioxane and 50 ml. of water to which a few crystals ofp-toluene-sulfonic acid were added. 10.3 gms. ofdibenzo[a,d]cyclohepta[1,4,6] trien-S-one were introduced portionwiseinto the reaction mixture solution. The solution was further stirred forabout 1 hour until all reactants had gone into solution. The solutionwas left standing at room temperature. After about 20 hours, the d,ltrans 10 hydroxy-ll-bromo-dibenzo[a,d]cyclohepta[1,4]dien-5-one began tocrystallize out. The ketone was filtered off and washed with 50 ml. ofwater. After recrystallization from acetic ester/cyclohexane, it meltedat 149 C.

From the motherand wash-liquor there can be isolated further portions ofthis compound by extraction with ether. Starting from10,11-epoxy-dibenzo[a,d]cyclohepta [l,4]dien5-one, the same compound wasobtained in the following way:

In a 5 liter four-necked round flask with stirrer, condenser, gas inlettube and dropping-funnel, 6 gms. of magnesium shavings were covered overwith ml. of absolute ether. After the addition of a grain of iodine, afew drops of a solution of 48 gms. of 1,2-dibromo-ethane in 600 ml. ofabsolute ether were added dropwise with the simultaneous introduction ofnitrogen gas and under constant stirring until the reaction mixturebeganboiling. The flow of the solution was so adjusted that the reactionmixture boiled moderately. After complete addition, the mixture washeated at reflux for an additional hour, whereby all the magnesium wentinto solution. A solution of 50 gms. of10,1l-epoxy-dibenzo[a,d]cyclohepta [1,4]dien-5-one in 4500 ml. ofabsolute ether was subsequently added to the mixture in one pouring. Thereaction mixture was heated under reflux conditions initially for 10hours and, after the addition of 100 ml. of dioxane, for an additional 5hours. After cooling, the dioxane- (magnesium bromide) complex wasfiltered off by suction and washed with 500 ml. of absolute ether. Thefiltrate was evaporated to dryness under reduced pressure. The residuewas dissolved in about ml. of acetic ester. The solution was filteredand treated at boiling heat with about 200 ml. of cyclohexane up to thebeginning of turbidity. The pure d,l trans 10 hydroxy-ll-bromo-dibenzo[a,d] cyclohepta 1,4] dien-S-one which crystallized out on coolingmelted at 149 C.

EXAMPLE 9 47.9 gms. of d,l -trans IO-hydroxy-ll-amino-dibenzo[a,d]cyclohepta[1,4]dien one (obtained as described above in Example1(a) were placed in a 1.5 liter sulfonation flask equipped with stirrer,reflux condenser, gas inlet tube, thermometer and dropping-funnel andsuspended in 900 ml. of chloroform. A solution of 108 gms. of thionylchloride in 100 ml. of chloroform was thereafter added dropwise withstirring at room temperature, the reaction being slightly exothermic.The reaction mixture was then heated at reflux temperature for 1 hour,whereby the ketone reactant dissolved with brown. coloration. Thissolution was cooled and poured on 500 gms. of ice. The organic phase wasseparated and washed twice with 200 ml. of water each time. The combinedaqueous solutions and extracts were shaken with active charcoal,filtered and made alkaline with 3 N aqueous ammonia with icecooling. Thecrude product which crystallized out was filtered off after a few hoursand washed neutral and chloride-free with water. Thed,l-cis-10chloro-1l-aminodibenzo[a,d]cyclohepta[1,4]dien-5-one melted at55 C. after recrystallization from dioxane/ethanol.

As described above, when employing d,l-trans-10-hydroxy 11 methylaminodibenzo[a,d]cyclohepta[1,4] dien-S-one (obtained according to Example1(-b)), there is obtained: d,l-cis-10-chloro-11-methy1amino-dibenzo[a,d]cyclohepta[l,4]dien-5-one, M.P. C. (decomposition).

EXAMPLE 10 12.0 gms. of d,l-trans-10-hydroxy-1l-amino-dibenzo[a,d]cyclohepta[1,4]dien-5-one (obtained according to Example 1(a)),were dissolved in 600 ml. of absolute tetrahydrofuran in a 1.5 litersulfonation flask with stirrer, thermometer and dropping-funnel andcooled to 0 C. At this temperature there was added dropwise 9 gms. oftriethylamine and subsequently a solution of 4 ml. of chloro-acetylchloride in 100 ml. of absolute tetrahydrofuran. The reaction mixturewas stirred for 2 hours at 0 C., made Congo-acid red with etherealhydrochloric acid and, after the addition of 600 ml. of absolute ether,filtered. The filter residue was washed with 200 ml. of absolute ether.The filtrate was concentrated to dryness under reduced pressure. Thed,l-trans-10-hydroxy-11- chloroacetamido dibenzo[a,d]cyclohepta[1,4]dien5- one which remained behind melted at 145 C. after recrystallizationfrom aqueous ethanol.

In an analogous manner, there was obtained according to the processdescribed above, when employing cyclopropyl carboxylic acid chloride:d,l-trans-lO-hydroxy- 11 cyclopropylcarbonylamido dibenzo[a,d]cyclohepta[l,4]dien-5-one, M.P. 171 C. (benzene); and when employing,B-chloro-propionic acid chloride: d,l-trans-lO- hydroxy 11 (3 chloropropionamido) dibenzo [a,d]cyclohepta[1,4]dien-5-one, M.P. 183-184 C.(benzene).

EXAMPLE 11 12.0 gms. of d,1-trans-l-hydroxy-ll-amino-dibenzo[a,d]cyclohepta[1,4]dien--one (obtained according to Example 1(a)) wasdissolved in 2000 ml. of chloroform and reacted with 7.1 gms. of benzoylchloride, 50 ml. of 1 N caustic soda and 250 ml. of water. The reactionmixture was shaken for 16 hours at room temperature. The organic phasewas separated and washed with 500 ml. of water, 500 ml. of 0.1 Nhydrochloric acid and three times with 500 ml. of water each time, driedover calcium chloride, filtered and evaporated to dryness under reducedpressure. The d,l-trans-lO-hydroxy- 11 benzamidodibenzo[a,d]cyclohepta[1,4]dien 5- one which remained behind melted at160 C. after recrystallization from aqueous methanol.

In an analogous manner, there was obtained according to the processdescribed immediately above when employing 2-methyl-propionyl chloride:d,l-trans-lO-hydroxy 11 (2 methyl propionamido) dibenzo[a,d]cyclohepta[1,4]dien-5-one, M.P. 225-226 C.

When reactingd,l-trans-lO-hydroxy-ll-methylaminodibenzo[a,d]cyclohepta[1,4]dien-5-one(obtained according to Example 1(b)) with p-chloro-propionyl chloride,in the manner described above, d,l-trans-LO-hydroxy-l 1- (N methyl N 3chloropropionamido) dibenzo[a, d]cyclohepta[1,4]dien-5-one, M.P. 207 C.(decomposition) was obtained.

When starting fromd,l-cis-lO-chloro-ll-methylaminodibenzo[a,d]cyclohepta[1,4]dien-5-one(obtained according to Example 6) in an analogous manner when employingB-chloropropionyl chloride there was obtained: d,l cis 10 chloro 11 (Nmethyl N 3 chloropropionamido)-dibenzo[a,d]cyclohepta[1,4] dien 5 one,M.P. 135-136 C.

EXAMPLE 12 amido)-dibenzo[a,d]cyclohepta[1,4]dien 5 one whichprecipitated was filtered oil and neutralized by washing with water.After recrystallization from ethanol, the compound melted at 174-175 C.(decomposition).

EXAMPLE 13 15 ml. of redistilled thionyl chloride were reacted in smallquantities while constantly stirring and cooling with 8.5 gms. ofd,l-trans-lO-hydroxy-ll-benzamido-dibenzo [a,d]cyclohepta[1,4]dien-5-one(obtained according to Example 10). With each small quantity of reactantadded to thionyl chloride enough time was allowed to elapse to achievecomplete solution. The reaction mixture was subsequently heated underreflux conditions at 50-55 C. for 2.5 hours and, after cooling, pouredinto 400 ml. of absolute ether. The 2-phenyl-dibenzo[a,d]cyclohepta[1,4] dien[f]oxazole-8-one hydrochloride formed was filtered off after 6hours, washed three times with 50 ml. of absolute ether each time and,without further purification, heated under reflux conditions for 5 hourswith ml.

of 3 N hydrochloric acid. After cooling, the precipitated benzoic acidwas filtered off and the filtrate was made alkaline, while stirring andcooling, with 3 N ammonia. The base,d,l-cis-10-hydroxy-1l-amino-dibenzo[a,d]cyclohepta[1,4]dien-5-one, whichprecipitated in crystalline form, was filtered off after a few hours andwashed three times with 50 ml. of water each time. The base melted at178-179 C. after recrystallization from ethanol.

EXAMPLE 14 12.0 gms. of d,l-trans-lO-hydroxy-ll-amino-dibenzo[a,d]cyclohepta[1,4]dien-5-one (obtained according to Example 1(a)) weredissolved in ml. of 3 N acetic acid and filtered. The filtrate wastreated with 10 gms. of acetic anhydride and heated for 10 minutes onthe steam bath. The base,d,l-trans-lO-hydroxy-ll-acetamidodibenzo[a,d]cyclohepta[ 1,4]dien-S-one, which precipitated on cooling, was filtered off afterstanding for 24 hours and washed neutral with water. The base melted at217 C. after recrystallization with aqueous ethanol.

In an analogous manner, there was obtained according to the processdescribed in Example 12, when employing d,l trans 10 hydroxy l1methylamino dibenzo [a,d]cyclohepta[1,4]dien-5-one (obtained accordingto Example 1(b) d 1 trans-10-hydroxy-l1-N-methyl-N- acetamidodibenzo[a,d]cyclohepta[1,4]dien-5-one, M.P. 256-258 C. (decomposition).When employing d,l-cis- 10 hydroxy 11 amino dibenzo[a,d]cyclohepta[1,4]dien-S-one (obtained according to Example 12): d,l-cis- 10 hydroxy 11acetamido dibenzo[a,d]cyclohepta [l,4]dien-5-one, M.P. 197-198 C.

EXAMPLE 15 2.4 gms. of d,l-trans-lO-hydroxy-l l-amino-dibenzo[a,d]cyclohepta[1,4]dien-5-one (obtained according to Example 1(a)) and 5gms. of acetic anhydride were reacted by heating at reflux temperaturefor 20 minutes. After cooling, the solution obtained was treated with 10ml. of water. After standing for several hours, the product, d,l-trans10-acetoxy 1l-acetamido-dibenzo[a,d]cyclohepta[1,4]dien-5-one, whichprecipitated, was filtered off and washed with water. The product meltedat 219-220 C. after recrystallization from ethanol.

In an analogous manner, there was obtained according to the processdescribed in this example when employing d,l-trans 10-hydroxyll-methylamino-dibenzo [a,d]cyclohepta[l,4]dien 5-one (obtainedaccording to Example 1(b)): d,l-trans 10-acetoxyll-N-methylacetamido-dibenzo[a,d]cyclohepta[1,4]dien 5-one, M.P. 142-145C.

EXAMPLE 16 12.0 gms. of d,l-trans 10-hydroxy ll-amino-dibenzo[a,d]cyclohepta[l,4]dien 5-one (obtained according to Example 1(a)) weredissolved in 200 ml. of 25% formic acid, filtered, reacted with 50 ml.of acetic anhydride and heated on the steam bath for 15 minutes. Aftercooling, the reaction mixture was treated with 100 ml. of water. Afterstanding for several hours, the product, d,l-trans IO-hydroxy11-formamido-dibenzo[a,d]cyclohepta[l,4]dien-5-one, crystallized out.After standing at room temperature for 24 hours, the product wasfiltered oil and washed neutral with water. After recrystallization fromaqueous ethanol the product melted at 205-206 C.

EXAMPLE 17 6 ml. of distilled thionyl chloride were placed in a St} ml.round flask and reacted in small quantities at a time, while constantlystirring and cooling, with 2.8 gms. of d,l-trans IO-hydroxy11-acetamido-dibenzo[a,d]cyclohepta[1,4]dien 5-one (obtained accordingto Example 13). With the addition of each small quantity of reactant tothe thionyl chloride, enough time was permitted to elapse until completedissolution was achieved. The reaction mixture was subsequently heatedunder reflux conditions at 50-55" C. for 2.5 hours, then cooled andpoured 13 into 150 ml. of absolute ether. The d,l-trans l-chloro- 11acetamido-dibenzo[a,d]cyclohepta[l,4]dien -one after recrystallizationfrom ethanol, melted at 205206 C. (decomposition).

' EXAMPLE 18 3.2 gms. of d,l-trans-l0-hydroxyll-chloroacetamidodibenzo[a,d] cyclohepta[1,4]dien-5-one (obtainedaccording to Example 9), 1.8 gms. of piperidine and 20 ml. of toluenewere reacted by heating under reflux conditions for 5 hours in a 50 ml.round flask with attached ascending tube. After cooling, 20 ml. of waterwere added. The organic phase was washed 5 times with 20 ml. of watereach time, dried over potassium carbonate and filtered. The filtrate wasmade congo-acid red with etherreal hydrochloric acid, whereby the crudehydrochloride crystallizes out.

The precipitation was made complete by the addition of 150 ml. ofabsolute ether and the reaction mixture was filtered after a few hours.The hygroscopic filter residue was further washed three times with 50ml. of absolute ether each time and dissolved in about 20 ml. of aqueousmethanol. The free base was obtained by the addition of 3 N aqueousammonia until alkaline pH was reached and then crystallized out byheating. The base, d,l-trans -hydroxy-11-(1-piperidino-acetamido)-dibenzo[a,d]cyclohepta[1,4]dien 5-one, thus obtained, melted at 90-91 C.after recrystallization from aqueous methanol.

7 EXAMPLE 19 13.0 gms. of d,l-cis-10-chloro 1l-amino-dibenzo[a,d]cyclohepta[1,4]dien 5-one (obtained according to Example -8) weredissolved with heating in 3600 ml. of about 95% ethanol in a *6 literErlenmeyer flask. The solution was filtered and, after the addition of1.5 gms. of 5% palladium/charcoal, hydrogenated with shaking at roomtemperature. After about 2 hours, the theoretical quantity of hydrogen(1 mole) was absorbed. The solution was separated from catalyst andevaporated to dryness under reduced pressure. The residue was dissolvedby heating in 40 ml. of ethanol. The solution was filtered and madealkaline with 3 N ammonia solution. The product,d,ll0-amino-dibenzo[a,d]cyclohepta [l,4]dien S-one, which crystallizedout on cooling, melted at 146 C. after recrystallization from ethanol.

According to the process described in Example 11, using this product asthe starting material, there was obtained d,l 10acetamido-dibenzo[a,d]cyclohepta[1,4]

dien-S-one.

EXAMPLE 3.0 gms. of d,l-1l-bromo-dibenzo[a,d]cyclohepta[1,4]diene-S-lO-dione were reacted with 2.2 gms. of N-methylpiperazine. Thereaction occurred immediately on heating. The reaction mixture wasfurther heated on the steam bath for 2 /2 hours, then cooled and treatedwith 20 ml. each of benzene and water, whereby, after vigorous shaking,complete solution was obtained. The benzene phase was washed 5 timeswith 20 ml. of water each time, dried over potassium carbonate andtreated with ethereal hydrochloric acid to congo-acid red reaction,whereby the hydrochloride crystallized out. The precipitation was madecomplete by the addition of 200 ml. of absolute ether. Thed,l-11-(4-methyl-piperazino)-dibenzo [a,d]cyclohepta[1,4]diene 5,10dione hydrochloride which was isolated after a few hours, afterrecrystallization from ethanol/ether, melted at 271 C. (decomposition).

According to the process described in this example, there was obtainedin an analogous manner when employing piperazine:d,l-11-piperazino-dibenzo[a,d]cyclo- 7 hepta[1,4]diene-5,10-dionehydrochloride, M.P. 291-292 EXAMPLE 21 1.5 gms. ofd,l-trans-l0-hydroxy-ll-piperidino-dibenzo[a,d]cycloheptal[1,4]dien-5-one (obtained according to Example 7) wereheated under reflux conditions for 15 minutes with 5 m1. of acetic acidanhydride. The solution was then poured, with constant stirring,'into 50ml. of water and made alkaline with 3 N ammonia. The crystals whichprecipitated were filtered off after a few hours and washed neutral withwater. The d,l-trans-10-acetoxyl1 piperidinodibenzo[a,d]cycloheptal[1,4]dien-5-one melted at 145 C. afterrecrystallization from methanol.

EXAMPLE 22 Manufacture of capsules of the following composition:

Mg. d,l Trans 2 imino-2,3;3a,12b-tetrahydro-8H-di benzo [3,4;6,7]cyclohept[ 1,2-d]oxazol.e-8-one 10 Mannitol 110 Talcum 5 The activematerial was homogeneously mixed with the talcum and mannitol, passedthrough a No. 5 sieve (mesh width about 0.23 mm.) and again thoroughlymixed. The mixture was filled into gelatin capsules size No. 4.

EXAMPLE 23 Manufacture of dragees of the following composition:

Mg. d,l Trans 2 imino-3-methyl-2,3;3a,IZb-tetrahydro8H-dibenzo[3,4;6,7]cyclohept[I,2-d]oxazole- 8-one 25 Mannitol Maizestarch 20 Talcum 5 The active material was mixed with mannitol andpassed through a No. 5 sieve (mesh width about 0.23 mm.). A 10% aqueouspaste was prepared from the maize starch and homogeneously mixed withthe active material which was mixed with mannitol. The slightly moistmass was passed through a No. 3 sieve (mesh width about 1.0 mm.). Thegranulate obtained was dried and, after the addition of the talcum,pressed to biconvex kernels with a weight of 150 mg. The kernelsobtained can be coated in the usual manner by coating with a sugarlayer.

EXAMPLE 24 Manufacture of capsules of the following composition:

Mg d,l 11 piperazino-dibenzo[a,d]cyclohepta[1,4]diene-5,10-dionehydrochloride 10 Mannitol Talcum 5 The active material was homogeneouslymixed with the talcum and mannitol, passed through a No. 5 sieve Theactive material was mixed with mannitol and passed through a No. sieve(mesh width about 0.23 mm.). A aqueous paste was prepared from the maizestarch and'homogeneously mixed with the active material which was mixedwith mannitol. The slightly moist mass was passed through a No. 3 sieve(mesh width about 1.0 mm.). The granulate obtained was dried and, afteraddition of the talcum, pressed to biconvex kernels with a Weight of 150mg. The kernels can be coated in the usual manner by coating with asugar layer.

(mesh width about 0.23 mm.) and again thoroughly mixed. The mixture wasfilled into gelatin capsules size EXAMPLE 25 Manufacture of dragees ofthe following composition: 5

. Mg. d,l Trans 10 hydroxy-l1-acetamino-dibenzo[a,d]

cyclohepta[1,4] dien-S-one 25 Mannitol 100 10 Maize starch Talcum 5 Weclaim: 1. A compound having the formula:

alkylenedioxy; R is hydrogen, lower alkyl, phenyl 16 or benzyl; R ishydrogen, lower alkyl, phenyl or benzyl; R taken together with R isthio, 0x0 or imino; R is hydrogen or lower alkyl and pharmaceuticallyacceptable acid addition salts thereof.

2. A compound of claim 1 which is 2-imin0-2,3;3a,12btetrahydro 8Hdibenzo[3,4;6,7]cyclohept[1,2 d]oxazole-8-one.

3. A compound of claim 1 which is 2-imino-3-methyl- 2,3;3a,12btetrahydro 8H dibenzo[3,4;6,7]cyclohept 1,2-d] oxazole-S-one.

4. A compound of claim 1 which is 3-methyl-2,3;3a, 12b tetrahydro 8Hdibenz0[3,4;6,7]cyclohept[1,2-d] oxazole-2,8-dione.

5. A compound of claim 1 which is 2,2,3-trimethyl-2,3; 3a,12b tetrahydro8H dibenzo[3,4;6,7]cyclohept[1,2- d]oxazole-8-one.

6. A compound of claim 1 which is 2-thio-3-methyl- 2,3;3a,12b tetrahydro8H dibenzo[3,4;6,7]cyclohept [1,2-d] oxazole-8-one.

7. A compound of claim 1 which is trans-2-phenyl-3 methyl 2,3 ;3a,1Zb-tetrahydro-SH-dibenzo[3,4;6,7] cyclohept[1,2-d]oxazole-8-one.

References Cited UNITED STATES PATENTS 2,985,660 5/1961 Judd et al.260-293 3,275,689 9/1966 Engelhardt 260-268 X 3,325,497 6/1967 Fouche260-268 3,332,977 7/1967 Wendler 260-268 X ALTON D. ROLLINS, PrimaryExaminer US. Cl. X.R.

3333 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent no.Lip-(83148 Dated November 11, 1969 Inve tor Edenhofer and Spiege bag Itis certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

r- In the formula in Column 3, line 65 Column 4, line 15 "Formula VII"should be Formula II Column 4, line 61 or any ether" should be or anether Column 10, line 32 in Example 9 "dien-one" should be dien-5-oneColumn 10, line 49 in Example 9 "at 55C" should be at 155C Column 14,line 2 in Example 20"cycloheptal" should be gyclohepta continued page 2@7 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,7 Dated Inventor(s) It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 14, line 9 in Example 20 "cycloheptal" should 1 cyclohepta Column14, line 16 in Example 21 "cycloheptal" should 1 gyclohepta Column 14,line 23 in Example 21 "oycloheptal" should I cyclohepta munifi 'ANDSE.'.LED

JAN 6 1971 BEN) Amt:

mm: 2. m. MgOffieor domissioner at Patonte

